{"gene":"ST14","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2001,"finding":"Crystal structures of the MT-SP1/matriptase catalytic domain were solved in complex with benzamidine (1.3 Å) and bovine pancreatic trypsin inhibitor (2.9 Å), revealing a trypsin-like serine proteinase fold with a unique nine-residue 60-insertion loop, a trypsin-like S1 pocket, a small hydrophobic S2 subsite, and an open negatively charged S4 cavity favoring basic P3/P4 residues. The structure also suggested a complementary charge pattern for docking of the preceding LDL receptor class A domain and served as a model for HAI-1 inhibitor interactions.","method":"X-ray crystallography (1.3 Å and 2.9 Å resolution crystal structures) with functional interpretation of active-site architecture","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures with two independent ligand complexes and active-site characterization in a single rigorous study","pmids":["11696548"],"is_preprint":false},{"year":2002,"finding":"Matriptase/MT-SP1 null mice die within 48 h of birth due to fatal dehydration caused by compromised epidermal barrier function (both inward and outward). Loss of the protease caused malformations of the stratum corneum (dysmorphic corneocytes, absence of vesicular bodies), follicular hypoplasia, absence of vibrissal hair canal formation, and dramatically increased thymocyte apoptosis with thymocyte depletion, establishing pleiotropic roles in epidermal development, hair follicle development, and thymic homeostasis.","method":"Germline knockout mouse (null mutation), histological and ultrastructural analysis, transepidermal water loss measurements","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean germline KO with multiple defined phenotypic readouts replicated across multiple organ systems in a single rigorous study","pmids":["12032844"],"is_preprint":false},{"year":2003,"finding":"Epidermal-specific deletion of Matriptase/MT-SP1 causes loss of proteolytically processed filaggrin monomers and the NH2-terminal filaggrin S-100 regulatory protein, with accumulation of profilaggrin and aberrant profilaggrin-processing products in the stratum corneum, identifying keratinocyte matriptase as an essential component of the profilaggrin-processing pathway. Epidermal deficiency also perturbed lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation.","method":"Conditional (epidermal) knockout mouse, proteomic analysis of epidermis, Western blotting","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with proteomic identification of substrate (profilaggrin processing) and multiple orthogonal readouts","pmids":["14638864"],"is_preprint":false},{"year":2007,"finding":"The ARIH-associated G827R missense mutation in the matriptase serine protease domain (G216 in chymotrypsin numbering) strongly reduces proteolytic activity toward small-molecule substrates and toward the candidate epidermal substrate prostasin. ST14 hypomorphic mice (100-fold reduced epidermal matriptase mRNA) phenocopy human ARIH with ichthyosis, hypotrichosis, and tooth defects, and display reduced prostasin proteolytic activation and reduced profilaggrin processing, consistent with a matriptase→prostasin proteolytic cascade operating in the epidermis.","method":"In vitro protease activity assay with G827R recombinant protein against small-molecule and protein substrates; ST14 hypomorphic mouse strain; biochemical analysis of epidermis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzyme assay with disease-associated mutant combined with a hypomorphic mouse model providing genetic validation and biochemical substrate data","pmids":["17940283"],"is_preprint":false},{"year":2008,"finding":"Mutations in ST14 (splice-site and frameshift) cause loss of matriptase protein in differentiated patient keratinocytes, reduced proteolytic activation of prostasin, and disturbed processing of profilaggrin in human ichthyosis-hypotrichosis patients, confirming the matriptase→prostasin→profilaggrin axis in human skin.","method":"Patient keratinocyte analysis (Western blot for matriptase and prostasin activation, profilaggrin processing assays), Sanger sequencing of ST14","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient loss-of-function corroborated by biochemical substrate analysis in primary cells; single lab but multiple orthogonal biochemical endpoints","pmids":["18843291"],"is_preprint":false},{"year":2001,"finding":"Rat MT-SP1 (ST14) expressed in Caco-2 cells localizes exclusively to the basolateral membrane surface; a secreted form of the enzyme produced in COS-1 cells degrades fibronectin and laminin in vitro, suggesting a role in regulating cell-substratum adhesion during intestinal epithelial turnover.","method":"Heterologous expression and immunolocalization (Caco-2); in vitro substrate cleavage assay (fibronectin, laminin) with secreted protease form","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization experiment combined with in vitro substrate cleavage; single lab, two orthogonal methods","pmids":["11573963"],"is_preprint":false},{"year":2006,"finding":"GST pull-down assays demonstrate that the ST14 serine protease (SP) domain physically interacts with HAI-1 (hepatocyte growth factor activator inhibitor-1). The CUB domain of ST14 interacts with TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1), and TMEFF1 expression is dependent on ST14 transfection in RKO cells; co-expression was confirmed in MCF7 cells and normal tissues.","method":"GST fusion protein pull-down assay; quantitative RT-PCR; homology modeling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — GST pull-down identifying two binding partners with corroborating expression data; single lab","pmids":["16407223"],"is_preprint":false},{"year":2007,"finding":"Two scFv antibody inhibitors of MT-SP1/matriptase inhibit the protease with K(I) values in the low picomolar range by competing with substrate at the S1 site. Alanine scanning of active-site loops defined distinct three-dimensional binding epitopes for each antibody. One inhibitor acts as a standard mechanism (substrate-like) inhibitor and can be processed by MT-SP1 at low pH.","method":"Kinetic inhibition assays; alanine scanning mutagenesis of active-site loops; antibody-based mechanistic characterization","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme kinetics with mutagenesis defining active-site contacts; single lab but multiple orthogonal methods","pmids":["17475279"],"is_preprint":false},{"year":2009,"finding":"ST14 overexpression in breast cancer cells reduces cell proliferation by upregulating p27, which results in downregulation of cyclin E-CDK2 complexes, thereby inhibiting S-phase entry. ST14 also reduces cell migration and invasion. Introduction of miR-27b into ST14-expressing cells did not suppress the cell-growth effect, indicating this cell-cycle regulatory function is independent of miR-27b regulation.","method":"Stable overexpression/knockdown; flow cytometry (cell cycle); Western blot (p27, cyclin E, CDK2); luciferase reporter assay for miR-27b target validation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined molecular pathway (p27/cyclin E-CDK2); single lab, multiple orthogonal readouts","pmids":["19546220"],"is_preprint":false},{"year":2010,"finding":"Epithin/PRSS14 (ST14) physically interacts with and proteolytically cleaves the extracellular domain of the angiopoietin receptor Tie2, degrading its ligand-binding domain. The remaining Tie2 fragment is highly phosphorylated and recruits PI3K. Knockdown of epithin in thymoma or breast cancer cells impairs transendothelial migration in vitro and reduces metastatic nodules in vivo.","method":"Co-immunoprecipitation; in vitro cleavage assay; shRNA knockdown; in vitro transendothelial migration assay; in vivo metastasis model (4T1)","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — substrate identified by co-IP and in vitro cleavage with functional validation by KD in vitro and in vivo using multiple orthogonal approaches","pmids":["21097670"],"is_preprint":false},{"year":2010,"finding":"Soluble (shed) epithin/PRSS14 secreted from cancer cells promotes endothelial cell migration and invasion, tube formation in vitro, and neovascularization in the chicken chorioallantoic membrane assay. Shed epithin is increased under hypoxia. Knockdown of epithin abolishes the protease activity of the secreted fraction and reduces endothelial invasion and tube formation, identifying secreted epithin as a proangiogenic factor.","method":"shRNA knockdown; endothelial migration/invasion assays; tube formation assay; CAM assay; specific antibody neutralization","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function combined with antibody neutralization and multiple functional readouts; single lab","pmids":["20652801"],"is_preprint":false},{"year":2011,"finding":"PRSS14/Epithin (ST14) is induced in macrophages by IFN-γ through the JAK/STAT1 pathway; ChIP confirmed that STAT1 binds two sites in the PRSS14/Epithin promoter upon IFN-γ activation. IFN-γ-treated macrophages show enhanced transendothelial migration that is abolished by PRSS14/Epithin knockdown, despite normal expression of ICAM1, CD80, and CD40.","method":"Chromatin immunoprecipitation (ChIP) for STAT1 binding; shRNA knockdown; JAK inhibitor (tyrphostin AG490); transendothelial migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validates transcriptional mechanism; KD provides functional readout; single lab, orthogonal methods","pmids":["21295011"],"is_preprint":false},{"year":2014,"finding":"Ectodomain shedding of epithin/PRSS14 is induced by TGF-β through a receptor-mediated pathway and is executed by TACE (tumor necrosis factor-α converting enzyme/ADAM17). TGF-β treatment induces translocation of intracellular TACE to the plasma membrane where epithin/PRSS14 resides. TACE inhibitor TAPI-0 and TACE siRNA greatly reduce TGF-β-induced shedding.","method":"TACE inhibitor treatment; TACE siRNA knockdown; Western blot for shedding products; immunofluorescence for TACE translocation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor and siRNA knockdown identify TACE as the sheddase; single lab, two orthogonal loss-of-function approaches","pmids":["25245289"],"is_preprint":false},{"year":2018,"finding":"A mitochondrial fraction of matriptase (ST14) in neural stem/progenitor cells co-immunoprecipitates with the β subunit of mitochondrial F0F1-ATP synthase (ATP-β), and this interaction was confirmed by co-immunofluorescence and in situ proximity ligation assay. The interaction requires both the CUB/CLR and LDL receptor motifs of matriptase. Knockdown of matriptase impairs mitochondrial membrane potential, reduces ATP synthesis and oxygen consumption rate (especially energy reserve capacity by >50%), and renders cells unable to tolerate hydrogen peroxide stress.","method":"Subcellular fractionation; co-immunoprecipitation; in situ proximity ligation assay; MitoTracker co-staining; mitochondrial respiration assay (Seahorse); shRNA knockdown","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mitochondrial localization confirmed by fractionation and co-staining, binding partner identified by co-IP and PLA, functional consequence measured by respiration assay; single lab but multiple orthogonal methods","pmids":["30566397"],"is_preprint":false},{"year":2018,"finding":"The transcription factor CDX2 regulates both ST14 (matriptase) and SPINT1 (HAI-1) gene expression in intestinal cells through distinct genomic enhancer elements identified by ChIP-seq. CDX2 shows both repressive and enhancing regulatory activity in a cell-specific manner and affects the ST14/SPINT1 mRNA ratio, thereby potentially controlling the oncogenic balance between matriptase and its inhibitor.","method":"CDX2 ChIP-seq; promoter-reporter luciferase assays; CDX2 overexpression/knockdown; quantitative RT-PCR","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq identifies regulatory elements, luciferase assays validate promoter activity; single lab, multiple orthogonal methods","pmids":["30087389"],"is_preprint":false},{"year":2020,"finding":"After ectodomain shedding of epithin/PRSS14, the remaining membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b (SPPL2b), releasing the intracellular domain (EICD) which preferentially localizes to the nucleus. Nuclear EICD enhances cancer cell migration, invasion, and metastasis and increases promoter activities of chemokines involved in cell motility (identified by RNA-seq and antibody arrays). This establishes a bidirectional signaling cascade: extracellular proteolysis by shed epithin and intracellular transcriptional reprogramming by EICD.","method":"SPPL2b knockdown/overexpression; subcellular fractionation and immunofluorescence; RNA-seq; antibody arrays; migration/invasion assays; in vivo metastasis; bioinformatics survival analysis","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — intramembrane protease identified by loss-of-function, EICD nuclear localization confirmed by fractionation and imaging, transcriptome reprogramming established by RNA-seq, functional consequences validated in vitro and in vivo; multiple orthogonal methods in single rigorous study","pmids":["32493324"],"is_preprint":false},{"year":2020,"finding":"JNK inhibition (SP600125) induces ectodomain shedding of Prss14/epithin via PKCβII and TACE. PKCβII is identified as a major mediator of both JNK inhibition- and PMA-induced shedding; loss-of-function using specific inhibitors, shRNA knockdown, and dominant-negative PKCβII variants all reduce shedding. SP600125 increases phosphorylation of PKCβII and TACE and induces their translocation to the plasma membrane where epithin/PRSS14 resides.","method":"MAP kinase inhibitor panel; shRNA knockdown; dominant-negative overexpression; Western blot for phosphorylation and shedding products; immunofluorescence for membrane translocation; in vitro invasion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple loss-of-function approaches converge on PKCβII→TACE pathway; single lab, multiple orthogonal methods","pmids":["32241917"],"is_preprint":false},{"year":2022,"finding":"Ectodomain shedding of epithin/PRSS14 in breast cancer 4T1 cells is induced by environmental selenite and increases CCL2 secretion in an epithin-dependent manner. Heterologous expression of the intracellular domain (EICD) alone is sufficient to induce CCL2 secretion, establishing that intramembrane proteolysis-mediated EICD release is responsible for the metastatic transcriptional effect downstream of ectodomain shedding.","method":"Selenite treatment; EICD heterologous expression; shRNA knockdown; ELISA for CCL2; invasion assay","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — environmental trigger identified, EICD sufficiency demonstrated by gain-of-function, CCL2 as downstream effector measured by ELISA; single lab","pmids":["35950457"],"is_preprint":false},{"year":2023,"finding":"Kidney-specific CAP3/St14 knockout mice show significantly decreased CAP1/Prss8 protein expression, altered ENaC subunit protein abundances, and decreased pNCC abundances, but maintain overall sodium balance. Double CAP1/Prss8; CAP3/St14 knockout mice restore ENaC subunit protein abundances but show reduced NCC activity under Na+ deprivation. RNAscope analysis confirmed co-expression of CAP3/St14 and CAP1/Prss8 with α-ENaC in distal tubules. The data establish that CAP3/St14 is NOT required for direct proteolytic activation of ENaC in vivo but regulates ENaC protein abundance, in part through controlling CAP1/Prss8 expression.","method":"Kidney-specific and double knockout mice; Western blot for ENaC/NCC subunit abundance; RNAscope in situ hybridization; sodium balance measurements; Na+-deprived diet challenge","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined molecular readouts (ENaC/NCC abundance and activity) and co-localization data; single lab, multiple orthogonal methods","pmids":["37830556"],"is_preprint":false},{"year":2005,"finding":"Post-translational processing of SNC19/ST14 (matriptase) in cancer cell lines produces at least two forms: a 120 kDa and a 75 kDa species. The 75 kDa form, identified using anti-His antibody after expression and purification, displays gelatinase (proteolytic) activity as assessed by gelatin zymography.","method":"Eukaryotic expression (Psectag2A-SNC19 ORF in BCAP37 cells); Western blot; gelatin zymography","journal":"Zhejiang da xue xue bao. Yi xue ban","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single zymography method; abstract is brief with limited methodological detail","pmids":["15693122"],"is_preprint":false},{"year":2019,"finding":"Prss14/ST14 knockdown in mouse breast cancer cells reduces metastasis (tumor nodules in vivo) without significantly affecting primary tumor growth in two syngeneic mouse models, and monoclonal antibody mAb3F3 targeting the autocatalytic loop epitope reduces cell migration and eliminates metastasis in MMTV-PyMT mice.","method":"shRNA knockdown; in vivo orthotopic/syngeneic tumor models (4T1, E0771, MMTV-PyMT); antibody treatment; cell migration assay; immunoprecipitation; flow cytometry","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and antibody blockade converge on metastasis function in vivo across multiple models; single lab","pmids":["31426843"],"is_preprint":false},{"year":2004,"finding":"Overexpression of SNC19/ST14 in RKO colorectal cancer cells alters F-actin (cytoskeletal) organization and decreases cell adhesion to extracellular matrix, without significantly changing cell cycle, apoptosis, or proliferation at moderate expression levels.","method":"Stable transfection; rhodamine-phalloidin confocal imaging of F-actin; MTT adhesion assay; flow cytometry","journal":"Zhonghua yi xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single gain-of-function in one cell line, limited mechanistic follow-up","pmids":["15200890"],"is_preprint":false}],"current_model":"ST14/matriptase is a type II transmembrane serine protease whose catalytic domain adopts a trypsin-like fold (crystal structure resolved) and cleaves substrates at basic P1 residues; it operates as an essential initiator of an epidermal matriptase→prostasin proteolytic cascade that drives profilaggrin processing, stratum corneum desquamation, and barrier formation, as demonstrated by knockout/hypomorphic mouse models and human disease mutations. The protease undergoes regulated ectodomain shedding mediated sequentially by PKCβII activation and TACE/ADAM17, after which SPPL2b executes intramembrane proteolysis to release an intracellular domain (EICD) that translocates to the nucleus and reprograms chemokine gene expression to promote cancer metastasis. Extracellularly, matriptase cleaves substrates including the Tie2 receptor ectodomain and fibronectin/laminin, and soluble shed epithin acts as a proangiogenic factor; in macrophages its expression is transcriptionally induced by IFN-γ via JAK/STAT1 to facilitate transendothelial migration. A mitochondrial pool of the protease binds the β-subunit of F0F1-ATP synthase via its CUB/LDL receptor domains and regulates mitochondrial bioenergetics in neural stem cells; in the kidney, St14 controls ENaC protein abundance indirectly through regulation of the co-protease CAP1/Prss8 rather than by direct ENaC cleavage."},"narrative":{"mechanistic_narrative":"ST14 (matriptase/epithin/MT-SP1) is a type II transmembrane serine protease that functions as the essential initiating protease of an epidermal proteolytic cascade controlling skin barrier formation, and as a multifunctional regulator of cancer cell motility and metastasis [PMID:12032844, PMID:14638864, PMID:32493324]. Its catalytic domain adopts a trypsin-like fold with an S4 cavity favoring basic P3/P4 residues, accounting for substrate cleavage at basic positions, and docks its preceding LDL-receptor-class-A domain and the inhibitor HAI-1 [PMID:11696548, PMID:16407223]. In the epidermis, matriptase proteolytically activates the downstream protease prostasin to drive profilaggrin processing, cornified envelope morphogenesis, lipid matrix formation, and stratum corneum desquamation; loss of this matriptase→prostasin→profilaggrin axis produces a fatal neonatal barrier defect in mice and underlies human autosomal recessive ichthyosis with hypotrichosis, caused by hypomorphic and loss-of-function ST14 mutations [PMID:12032844, PMID:14638864, PMID:17940283, PMID:18843291]. The protease is regulated by ectodomain shedding executed sequentially through PKCβII and TACE/ADAM17 and triggered by TGF-β, JNK inhibition, or environmental selenite; the membrane stub is then cleaved by the intramembrane protease SPPL2b to release an intracellular domain (EICD) that translocates to the nucleus and reprograms chemokine genes including CCL2 to promote migration, invasion, and metastasis [PMID:25245289, PMID:32493324, PMID:32241917, PMID:35950457]. Extracellularly, matriptase cleaves the Tie2 receptor ectodomain, degrades fibronectin and laminin, and the shed soluble form acts as a proangiogenic factor, while in macrophages its expression is induced by IFN-γ via JAK/STAT1 to enable transendothelial migration [PMID:11573963, PMID:21097670, PMID:20652801, PMID:21295011]. A mitochondrial pool binds the β subunit of F0F1-ATP synthase through its CUB and LDL-receptor motifs to sustain bioenergetics in neural stem cells, and in kidney St14 controls ENaC subunit abundance indirectly by regulating the co-protease CAP1/Prss8 rather than by direct ENaC cleavage [PMID:30566397, PMID:37830556].","teleology":[{"year":2001,"claim":"Establishing the catalytic-domain architecture explained how matriptase achieves trypsin-like specificity and revealed how its accessory domains and the inhibitor HAI-1 engage the active site.","evidence":"High-resolution X-ray crystal structures of the catalytic domain with benzamidine and BPTI","pmids":["11696548"],"confidence":"High","gaps":["Structure of the full-length multidomain transmembrane protease not resolved","Conformational basis of zymogen activation not addressed"]},{"year":2002,"claim":"Germline knockout revealed that matriptase is essential for epidermal barrier formation and demonstrated pleiotropic developmental roles, framing it as a physiologically critical protease rather than merely a cancer-associated enzyme.","evidence":"Null mouse with histological, ultrastructural, and transepidermal water loss analyses","pmids":["12032844"],"confidence":"High","gaps":["Molecular substrates underlying barrier defect not identified in this study","Mechanism of thymocyte apoptosis unexplained"]},{"year":2003,"claim":"Epidermal-specific deletion identified profilaggrin processing as a key downstream pathway, placing matriptase within keratinocyte differentiation biochemistry.","evidence":"Conditional epidermal knockout mouse with epidermal proteomics and Western blotting","pmids":["14638864"],"confidence":"High","gaps":["Direct vs indirect cleavage of profilaggrin not distinguished","Intermediate proteases between matriptase and filaggrin not yet defined"]},{"year":2007,"claim":"A disease-associated catalytic mutant and hypomorphic mice tied reduced enzymatic activity to defective prostasin activation, defining the matriptase→prostasin cascade and genetically validating the human disease link.","evidence":"In vitro activity assay of G827R mutant plus ST14 hypomorphic mouse phenotyping","pmids":["17940283"],"confidence":"High","gaps":["Whether prostasin is a direct matriptase substrate not fully resolved in vivo","Other epidermal substrates not excluded"]},{"year":2008,"claim":"Human patient mutations confirmed that loss of matriptase impairs prostasin activation and profilaggrin processing, translating the murine cascade to human ichthyosis-hypotrichosis.","evidence":"Patient keratinocyte Western blots and ST14 sequencing","pmids":["18843291"],"confidence":"Medium","gaps":["Single lab; biochemical readouts not reconstituted in vitro","Genotype-phenotype range across patients limited"]},{"year":2001,"claim":"Polarized basolateral localization and degradation of matrix proteins suggested a role in epithelial cell-substratum adhesion, the earliest hint of extracellular substrate function.","evidence":"Heterologous expression/immunolocalization in Caco-2 and in vitro fibronectin/laminin cleavage","pmids":["11573963"],"confidence":"Medium","gaps":["In vitro cleavage not validated as physiological substrate","Single-lab, heterologous system"]},{"year":2006,"claim":"Domain-resolved interaction mapping showed the serine protease domain binds HAI-1 and the CUB domain binds TMEFF1, beginning to define matriptase's regulatory and binding partners.","evidence":"GST pull-down, qRT-PCR and homology modeling in RKO/MCF7 cells","pmids":["16407223"],"confidence":"Medium","gaps":["Functional consequence of TMEFF1 interaction unclear","Pull-downs not reciprocally validated in vivo"]},{"year":2007,"claim":"Engineered scFv inhibitors with mapped active-site epitopes established that matriptase is druggable at the S1 substrate-binding site, providing mechanistic tools.","evidence":"Kinetic inhibition assays and alanine-scanning mutagenesis of active-site loops","pmids":["17475279"],"confidence":"High","gaps":["Therapeutic efficacy in vivo not addressed here","Specificity against related proteases not detailed"]},{"year":2009,"claim":"Gain/loss-of-function in breast cancer cells linked ST14 to cell-cycle restraint via p27/cyclin E-CDK2, indicating context-dependent anti-proliferative effects independent of miR-27b.","evidence":"Overexpression/knockdown with flow cytometry, Western blot and luciferase reporter","pmids":["19546220"],"confidence":"Medium","gaps":["Whether protease activity mediates the cell-cycle effect not resolved","Reconciliation with pro-metastatic roles unaddressed"]},{"year":2010,"claim":"Identification of Tie2 as a cleaved substrate and of shed soluble matriptase as a proangiogenic factor connected the protease to vascular remodeling and metastatic dissemination.","evidence":"Co-IP, in vitro cleavage, shRNA knockdown, transendothelial migration, CAM assay and in vivo metastasis","pmids":["21097670","20652801"],"confidence":"High","gaps":["In vivo relevance of Tie2 cleavage vs other substrates not quantified","Identity of the proangiogenic shed substrate not pinpointed"]},{"year":2011,"claim":"Transcriptional induction by IFN-γ through JAK/STAT1 established a regulatory input controlling matriptase expression in immune cells and its role in macrophage transendothelial migration.","evidence":"STAT1 ChIP, JAK inhibitor, shRNA knockdown and migration assays","pmids":["21295011"],"confidence":"Medium","gaps":["Macrophage substrate driving migration not identified","Single lab"]},{"year":2018,"claim":"CDX2-dependent regulation of ST14 and SPINT1 via distinct enhancers revealed transcriptional control of the protease/inhibitor balance in intestinal cells.","evidence":"CDX2 ChIP-seq, luciferase reporters, overexpression/knockdown and qRT-PCR","pmids":["30087389"],"confidence":"Medium","gaps":["Functional oncogenic consequence of altered ratio not demonstrated","Cell-specific repressive vs enhancing logic not mechanistically explained"]},{"year":2018,"claim":"A mitochondrial pool binding ATP synthase β subunit via CUB/LDL motifs revealed an unexpected non-proteolytic bioenergetic function in neural stem cells.","evidence":"Fractionation, co-IP, proximity ligation, MitoTracker co-staining and Seahorse respiration with knockdown","pmids":["30566397"],"confidence":"Medium","gaps":["Mechanism of mitochondrial targeting unknown","Whether catalytic activity is involved unresolved","Single lab"]},{"year":2020,"claim":"Sequential PKCβII/TACE shedding followed by SPPL2b intramembrane proteolysis releasing a nuclear EICD established a bidirectional signaling cascade coupling extracellular proteolysis to transcriptional reprogramming of chemokines driving metastasis.","evidence":"Inhibitor/siRNA/dominant-negative shedding analyses, SPPL2b loss/gain-of-function, fractionation, RNA-seq, antibody arrays and in vivo metastasis","pmids":["32493324","32241917","25245289"],"confidence":"High","gaps":["Nuclear partners and DNA-binding mode of EICD undefined","Direct vs indirect chemokine promoter regulation not established"]},{"year":2022,"claim":"Demonstrating that environmental selenite triggers shedding and that EICD alone is sufficient to induce CCL2 secretion pinpointed the intracellular fragment as the effector of the pro-metastatic transcriptional response.","evidence":"Selenite treatment, EICD heterologous expression, shRNA knockdown, CCL2 ELISA and invasion assay in 4T1 cells","pmids":["35950457"],"confidence":"Medium","gaps":["Generality of selenite trigger across tissues unknown","Mechanism by which EICD activates CCL2 promoter not defined"]},{"year":2019,"claim":"Knockdown and antibody blockade established matriptase as a metastasis-selective target whose inhibition spares primary tumor growth, supporting therapeutic targeting of the autocatalytic loop epitope.","evidence":"shRNA and mAb3F3 treatment in 4T1, E0771 and MMTV-PyMT models with migration assays","pmids":["31426843"],"confidence":"Medium","gaps":["Molecular target of mAb-induced inhibition not biochemically detailed","Single lab"]},{"year":2023,"claim":"Kidney-specific and double knockouts showed St14 regulates ENaC subunit abundance indirectly through the co-protease CAP1/Prss8 rather than by direct ENaC cleavage, refining its role in renal sodium handling.","evidence":"Tissue-specific and double KO mice with Western blots, RNAscope, sodium balance and Na+-deprivation challenge","pmids":["37830556"],"confidence":"Medium","gaps":["Mechanism by which St14 controls CAP1/Prss8 abundance unknown","Physiological significance limited as sodium balance is maintained"]},{"year":null,"claim":"How the same protease reconciles anti-proliferative, pro-metastatic, mitochondrial, and barrier-forming activities, and what governs tissue-specific substrate selection and subcellular targeting, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model integrating extracellular, intramembrane, nuclear, and mitochondrial functions","Tissue-specific substrate repertoire incompletely defined","Regulatory switch between tumor-suppressive and tumor-promoting outputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,5,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,9,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[15,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,12,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15,17]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11]}],"complexes":[],"partners":["SPINT1","TMEFF1","TEK","ADAM17","SPPL2B","PRSS8","ATP5F1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5Y6","full_name":"Suppressor of tumorigenicity 14 protein","aliases":["Matriptase","Membrane-type serine protease 1","MT-SP1","Prostamin","Serine protease 14","Serine protease TADG-15","Tumor-associated differentially-expressed gene 15 protein"],"length_aa":855,"mass_kda":94.8,"function":"Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site (PubMed:10373424). Involved in the terminal differentiation of keratinocytes through prostasin (PRSS8) activation and filaggrin (FLG) processing (PubMed:18843291). 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The structure also suggested a complementary charge pattern for docking of the preceding LDL receptor class A domain and served as a model for HAI-1 inhibitor interactions.\",\n      \"method\": \"X-ray crystallography (1.3 Å and 2.9 Å resolution crystal structures) with functional interpretation of active-site architecture\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures with two independent ligand complexes and active-site characterization in a single rigorous study\",\n      \"pmids\": [\"11696548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Matriptase/MT-SP1 null mice die within 48 h of birth due to fatal dehydration caused by compromised epidermal barrier function (both inward and outward). Loss of the protease caused malformations of the stratum corneum (dysmorphic corneocytes, absence of vesicular bodies), follicular hypoplasia, absence of vibrissal hair canal formation, and dramatically increased thymocyte apoptosis with thymocyte depletion, establishing pleiotropic roles in epidermal development, hair follicle development, and thymic homeostasis.\",\n      \"method\": \"Germline knockout mouse (null mutation), histological and ultrastructural analysis, transepidermal water loss measurements\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean germline KO with multiple defined phenotypic readouts replicated across multiple organ systems in a single rigorous study\",\n      \"pmids\": [\"12032844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Epidermal-specific deletion of Matriptase/MT-SP1 causes loss of proteolytically processed filaggrin monomers and the NH2-terminal filaggrin S-100 regulatory protein, with accumulation of profilaggrin and aberrant profilaggrin-processing products in the stratum corneum, identifying keratinocyte matriptase as an essential component of the profilaggrin-processing pathway. Epidermal deficiency also perturbed lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation.\",\n      \"method\": \"Conditional (epidermal) knockout mouse, proteomic analysis of epidermis, Western blotting\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with proteomic identification of substrate (profilaggrin processing) and multiple orthogonal readouts\",\n      \"pmids\": [\"14638864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The ARIH-associated G827R missense mutation in the matriptase serine protease domain (G216 in chymotrypsin numbering) strongly reduces proteolytic activity toward small-molecule substrates and toward the candidate epidermal substrate prostasin. ST14 hypomorphic mice (100-fold reduced epidermal matriptase mRNA) phenocopy human ARIH with ichthyosis, hypotrichosis, and tooth defects, and display reduced prostasin proteolytic activation and reduced profilaggrin processing, consistent with a matriptase→prostasin proteolytic cascade operating in the epidermis.\",\n      \"method\": \"In vitro protease activity assay with G827R recombinant protein against small-molecule and protein substrates; ST14 hypomorphic mouse strain; biochemical analysis of epidermis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzyme assay with disease-associated mutant combined with a hypomorphic mouse model providing genetic validation and biochemical substrate data\",\n      \"pmids\": [\"17940283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mutations in ST14 (splice-site and frameshift) cause loss of matriptase protein in differentiated patient keratinocytes, reduced proteolytic activation of prostasin, and disturbed processing of profilaggrin in human ichthyosis-hypotrichosis patients, confirming the matriptase→prostasin→profilaggrin axis in human skin.\",\n      \"method\": \"Patient keratinocyte analysis (Western blot for matriptase and prostasin activation, profilaggrin processing assays), Sanger sequencing of ST14\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient loss-of-function corroborated by biochemical substrate analysis in primary cells; single lab but multiple orthogonal biochemical endpoints\",\n      \"pmids\": [\"18843291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Rat MT-SP1 (ST14) expressed in Caco-2 cells localizes exclusively to the basolateral membrane surface; a secreted form of the enzyme produced in COS-1 cells degrades fibronectin and laminin in vitro, suggesting a role in regulating cell-substratum adhesion during intestinal epithelial turnover.\",\n      \"method\": \"Heterologous expression and immunolocalization (Caco-2); in vitro substrate cleavage assay (fibronectin, laminin) with secreted protease form\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization experiment combined with in vitro substrate cleavage; single lab, two orthogonal methods\",\n      \"pmids\": [\"11573963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GST pull-down assays demonstrate that the ST14 serine protease (SP) domain physically interacts with HAI-1 (hepatocyte growth factor activator inhibitor-1). The CUB domain of ST14 interacts with TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1), and TMEFF1 expression is dependent on ST14 transfection in RKO cells; co-expression was confirmed in MCF7 cells and normal tissues.\",\n      \"method\": \"GST fusion protein pull-down assay; quantitative RT-PCR; homology modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — GST pull-down identifying two binding partners with corroborating expression data; single lab\",\n      \"pmids\": [\"16407223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Two scFv antibody inhibitors of MT-SP1/matriptase inhibit the protease with K(I) values in the low picomolar range by competing with substrate at the S1 site. Alanine scanning of active-site loops defined distinct three-dimensional binding epitopes for each antibody. One inhibitor acts as a standard mechanism (substrate-like) inhibitor and can be processed by MT-SP1 at low pH.\",\n      \"method\": \"Kinetic inhibition assays; alanine scanning mutagenesis of active-site loops; antibody-based mechanistic characterization\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme kinetics with mutagenesis defining active-site contacts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17475279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ST14 overexpression in breast cancer cells reduces cell proliferation by upregulating p27, which results in downregulation of cyclin E-CDK2 complexes, thereby inhibiting S-phase entry. ST14 also reduces cell migration and invasion. Introduction of miR-27b into ST14-expressing cells did not suppress the cell-growth effect, indicating this cell-cycle regulatory function is independent of miR-27b regulation.\",\n      \"method\": \"Stable overexpression/knockdown; flow cytometry (cell cycle); Western blot (p27, cyclin E, CDK2); luciferase reporter assay for miR-27b target validation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined molecular pathway (p27/cyclin E-CDK2); single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"19546220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Epithin/PRSS14 (ST14) physically interacts with and proteolytically cleaves the extracellular domain of the angiopoietin receptor Tie2, degrading its ligand-binding domain. The remaining Tie2 fragment is highly phosphorylated and recruits PI3K. Knockdown of epithin in thymoma or breast cancer cells impairs transendothelial migration in vitro and reduces metastatic nodules in vivo.\",\n      \"method\": \"Co-immunoprecipitation; in vitro cleavage assay; shRNA knockdown; in vitro transendothelial migration assay; in vivo metastasis model (4T1)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — substrate identified by co-IP and in vitro cleavage with functional validation by KD in vitro and in vivo using multiple orthogonal approaches\",\n      \"pmids\": [\"21097670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Soluble (shed) epithin/PRSS14 secreted from cancer cells promotes endothelial cell migration and invasion, tube formation in vitro, and neovascularization in the chicken chorioallantoic membrane assay. Shed epithin is increased under hypoxia. Knockdown of epithin abolishes the protease activity of the secreted fraction and reduces endothelial invasion and tube formation, identifying secreted epithin as a proangiogenic factor.\",\n      \"method\": \"shRNA knockdown; endothelial migration/invasion assays; tube formation assay; CAM assay; specific antibody neutralization\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function combined with antibody neutralization and multiple functional readouts; single lab\",\n      \"pmids\": [\"20652801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PRSS14/Epithin (ST14) is induced in macrophages by IFN-γ through the JAK/STAT1 pathway; ChIP confirmed that STAT1 binds two sites in the PRSS14/Epithin promoter upon IFN-γ activation. IFN-γ-treated macrophages show enhanced transendothelial migration that is abolished by PRSS14/Epithin knockdown, despite normal expression of ICAM1, CD80, and CD40.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for STAT1 binding; shRNA knockdown; JAK inhibitor (tyrphostin AG490); transendothelial migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validates transcriptional mechanism; KD provides functional readout; single lab, orthogonal methods\",\n      \"pmids\": [\"21295011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ectodomain shedding of epithin/PRSS14 is induced by TGF-β through a receptor-mediated pathway and is executed by TACE (tumor necrosis factor-α converting enzyme/ADAM17). TGF-β treatment induces translocation of intracellular TACE to the plasma membrane where epithin/PRSS14 resides. TACE inhibitor TAPI-0 and TACE siRNA greatly reduce TGF-β-induced shedding.\",\n      \"method\": \"TACE inhibitor treatment; TACE siRNA knockdown; Western blot for shedding products; immunofluorescence for TACE translocation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor and siRNA knockdown identify TACE as the sheddase; single lab, two orthogonal loss-of-function approaches\",\n      \"pmids\": [\"25245289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A mitochondrial fraction of matriptase (ST14) in neural stem/progenitor cells co-immunoprecipitates with the β subunit of mitochondrial F0F1-ATP synthase (ATP-β), and this interaction was confirmed by co-immunofluorescence and in situ proximity ligation assay. The interaction requires both the CUB/CLR and LDL receptor motifs of matriptase. Knockdown of matriptase impairs mitochondrial membrane potential, reduces ATP synthesis and oxygen consumption rate (especially energy reserve capacity by >50%), and renders cells unable to tolerate hydrogen peroxide stress.\",\n      \"method\": \"Subcellular fractionation; co-immunoprecipitation; in situ proximity ligation assay; MitoTracker co-staining; mitochondrial respiration assay (Seahorse); shRNA knockdown\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mitochondrial localization confirmed by fractionation and co-staining, binding partner identified by co-IP and PLA, functional consequence measured by respiration assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30566397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The transcription factor CDX2 regulates both ST14 (matriptase) and SPINT1 (HAI-1) gene expression in intestinal cells through distinct genomic enhancer elements identified by ChIP-seq. CDX2 shows both repressive and enhancing regulatory activity in a cell-specific manner and affects the ST14/SPINT1 mRNA ratio, thereby potentially controlling the oncogenic balance between matriptase and its inhibitor.\",\n      \"method\": \"CDX2 ChIP-seq; promoter-reporter luciferase assays; CDX2 overexpression/knockdown; quantitative RT-PCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq identifies regulatory elements, luciferase assays validate promoter activity; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30087389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"After ectodomain shedding of epithin/PRSS14, the remaining membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b (SPPL2b), releasing the intracellular domain (EICD) which preferentially localizes to the nucleus. Nuclear EICD enhances cancer cell migration, invasion, and metastasis and increases promoter activities of chemokines involved in cell motility (identified by RNA-seq and antibody arrays). This establishes a bidirectional signaling cascade: extracellular proteolysis by shed epithin and intracellular transcriptional reprogramming by EICD.\",\n      \"method\": \"SPPL2b knockdown/overexpression; subcellular fractionation and immunofluorescence; RNA-seq; antibody arrays; migration/invasion assays; in vivo metastasis; bioinformatics survival analysis\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — intramembrane protease identified by loss-of-function, EICD nuclear localization confirmed by fractionation and imaging, transcriptome reprogramming established by RNA-seq, functional consequences validated in vitro and in vivo; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"32493324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JNK inhibition (SP600125) induces ectodomain shedding of Prss14/epithin via PKCβII and TACE. PKCβII is identified as a major mediator of both JNK inhibition- and PMA-induced shedding; loss-of-function using specific inhibitors, shRNA knockdown, and dominant-negative PKCβII variants all reduce shedding. SP600125 increases phosphorylation of PKCβII and TACE and induces their translocation to the plasma membrane where epithin/PRSS14 resides.\",\n      \"method\": \"MAP kinase inhibitor panel; shRNA knockdown; dominant-negative overexpression; Western blot for phosphorylation and shedding products; immunofluorescence for membrane translocation; in vitro invasion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple loss-of-function approaches converge on PKCβII→TACE pathway; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32241917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ectodomain shedding of epithin/PRSS14 in breast cancer 4T1 cells is induced by environmental selenite and increases CCL2 secretion in an epithin-dependent manner. Heterologous expression of the intracellular domain (EICD) alone is sufficient to induce CCL2 secretion, establishing that intramembrane proteolysis-mediated EICD release is responsible for the metastatic transcriptional effect downstream of ectodomain shedding.\",\n      \"method\": \"Selenite treatment; EICD heterologous expression; shRNA knockdown; ELISA for CCL2; invasion assay\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — environmental trigger identified, EICD sufficiency demonstrated by gain-of-function, CCL2 as downstream effector measured by ELISA; single lab\",\n      \"pmids\": [\"35950457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kidney-specific CAP3/St14 knockout mice show significantly decreased CAP1/Prss8 protein expression, altered ENaC subunit protein abundances, and decreased pNCC abundances, but maintain overall sodium balance. Double CAP1/Prss8; CAP3/St14 knockout mice restore ENaC subunit protein abundances but show reduced NCC activity under Na+ deprivation. RNAscope analysis confirmed co-expression of CAP3/St14 and CAP1/Prss8 with α-ENaC in distal tubules. The data establish that CAP3/St14 is NOT required for direct proteolytic activation of ENaC in vivo but regulates ENaC protein abundance, in part through controlling CAP1/Prss8 expression.\",\n      \"method\": \"Kidney-specific and double knockout mice; Western blot for ENaC/NCC subunit abundance; RNAscope in situ hybridization; sodium balance measurements; Na+-deprived diet challenge\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined molecular readouts (ENaC/NCC abundance and activity) and co-localization data; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37830556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Post-translational processing of SNC19/ST14 (matriptase) in cancer cell lines produces at least two forms: a 120 kDa and a 75 kDa species. The 75 kDa form, identified using anti-His antibody after expression and purification, displays gelatinase (proteolytic) activity as assessed by gelatin zymography.\",\n      \"method\": \"Eukaryotic expression (Psectag2A-SNC19 ORF in BCAP37 cells); Western blot; gelatin zymography\",\n      \"journal\": \"Zhejiang da xue xue bao. Yi xue ban\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single zymography method; abstract is brief with limited methodological detail\",\n      \"pmids\": [\"15693122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Prss14/ST14 knockdown in mouse breast cancer cells reduces metastasis (tumor nodules in vivo) without significantly affecting primary tumor growth in two syngeneic mouse models, and monoclonal antibody mAb3F3 targeting the autocatalytic loop epitope reduces cell migration and eliminates metastasis in MMTV-PyMT mice.\",\n      \"method\": \"shRNA knockdown; in vivo orthotopic/syngeneic tumor models (4T1, E0771, MMTV-PyMT); antibody treatment; cell migration assay; immunoprecipitation; flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and antibody blockade converge on metastasis function in vivo across multiple models; single lab\",\n      \"pmids\": [\"31426843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Overexpression of SNC19/ST14 in RKO colorectal cancer cells alters F-actin (cytoskeletal) organization and decreases cell adhesion to extracellular matrix, without significantly changing cell cycle, apoptosis, or proliferation at moderate expression levels.\",\n      \"method\": \"Stable transfection; rhodamine-phalloidin confocal imaging of F-actin; MTT adhesion assay; flow cytometry\",\n      \"journal\": \"Zhonghua yi xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single gain-of-function in one cell line, limited mechanistic follow-up\",\n      \"pmids\": [\"15200890\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ST14/matriptase is a type II transmembrane serine protease whose catalytic domain adopts a trypsin-like fold (crystal structure resolved) and cleaves substrates at basic P1 residues; it operates as an essential initiator of an epidermal matriptase→prostasin proteolytic cascade that drives profilaggrin processing, stratum corneum desquamation, and barrier formation, as demonstrated by knockout/hypomorphic mouse models and human disease mutations. The protease undergoes regulated ectodomain shedding mediated sequentially by PKCβII activation and TACE/ADAM17, after which SPPL2b executes intramembrane proteolysis to release an intracellular domain (EICD) that translocates to the nucleus and reprograms chemokine gene expression to promote cancer metastasis. Extracellularly, matriptase cleaves substrates including the Tie2 receptor ectodomain and fibronectin/laminin, and soluble shed epithin acts as a proangiogenic factor; in macrophages its expression is transcriptionally induced by IFN-γ via JAK/STAT1 to facilitate transendothelial migration. A mitochondrial pool of the protease binds the β-subunit of F0F1-ATP synthase via its CUB/LDL receptor domains and regulates mitochondrial bioenergetics in neural stem cells; in the kidney, St14 controls ENaC protein abundance indirectly through regulation of the co-protease CAP1/Prss8 rather than by direct ENaC cleavage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ST14 (matriptase/epithin/MT-SP1) is a type II transmembrane serine protease that functions as the essential initiating protease of an epidermal proteolytic cascade controlling skin barrier formation, and as a multifunctional regulator of cancer cell motility and metastasis [#1, #2, #15]. Its catalytic domain adopts a trypsin-like fold with an S4 cavity favoring basic P3/P4 residues, accounting for substrate cleavage at basic positions, and docks its preceding LDL-receptor-class-A domain and the inhibitor HAI-1 [#0, #6]. In the epidermis, matriptase proteolytically activates the downstream protease prostasin to drive profilaggrin processing, cornified envelope morphogenesis, lipid matrix formation, and stratum corneum desquamation; loss of this matriptase\\u2192prostasin\\u2192profilaggrin axis produces a fatal neonatal barrier defect in mice and underlies human autosomal recessive ichthyosis with hypotrichosis, caused by hypomorphic and loss-of-function ST14 mutations [#1, #2, #3, #4]. The protease is regulated by ectodomain shedding executed sequentially through PKC\\u03b2II and TACE/ADAM17 and triggered by TGF-\\u03b2, JNK inhibition, or environmental selenite; the membrane stub is then cleaved by the intramembrane protease SPPL2b to release an intracellular domain (EICD) that translocates to the nucleus and reprograms chemokine genes including CCL2 to promote migration, invasion, and metastasis [#12, #15, #16, #17]. Extracellularly, matriptase cleaves the Tie2 receptor ectodomain, degrades fibronectin and laminin, and the shed soluble form acts as a proangiogenic factor, while in macrophages its expression is induced by IFN-\\u03b3 via JAK/STAT1 to enable transendothelial migration [#5, #9, #10, #11]. A mitochondrial pool binds the \\u03b2 subunit of F0F1-ATP synthase through its CUB and LDL-receptor motifs to sustain bioenergetics in neural stem cells, and in kidney St14 controls ENaC subunit abundance indirectly by regulating the co-protease CAP1/Prss8 rather than by direct ENaC cleavage [#13, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing the catalytic-domain architecture explained how matriptase achieves trypsin-like specificity and revealed how its accessory domains and the inhibitor HAI-1 engage the active site.\",\n      \"evidence\": \"High-resolution X-ray crystal structures of the catalytic domain with benzamidine and BPTI\",\n      \"pmids\": [\"11696548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full-length multidomain transmembrane protease not resolved\", \"Conformational basis of zymogen activation not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Germline knockout revealed that matriptase is essential for epidermal barrier formation and demonstrated pleiotropic developmental roles, framing it as a physiologically critical protease rather than merely a cancer-associated enzyme.\",\n      \"evidence\": \"Null mouse with histological, ultrastructural, and transepidermal water loss analyses\",\n      \"pmids\": [\"12032844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrates underlying barrier defect not identified in this study\", \"Mechanism of thymocyte apoptosis unexplained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Epidermal-specific deletion identified profilaggrin processing as a key downstream pathway, placing matriptase within keratinocyte differentiation biochemistry.\",\n      \"evidence\": \"Conditional epidermal knockout mouse with epidermal proteomics and Western blotting\",\n      \"pmids\": [\"14638864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect cleavage of profilaggrin not distinguished\", \"Intermediate proteases between matriptase and filaggrin not yet defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A disease-associated catalytic mutant and hypomorphic mice tied reduced enzymatic activity to defective prostasin activation, defining the matriptase\\u2192prostasin cascade and genetically validating the human disease link.\",\n      \"evidence\": \"In vitro activity assay of G827R mutant plus ST14 hypomorphic mouse phenotyping\",\n      \"pmids\": [\"17940283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether prostasin is a direct matriptase substrate not fully resolved in vivo\", \"Other epidermal substrates not excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Human patient mutations confirmed that loss of matriptase impairs prostasin activation and profilaggrin processing, translating the murine cascade to human ichthyosis-hypotrichosis.\",\n      \"evidence\": \"Patient keratinocyte Western blots and ST14 sequencing\",\n      \"pmids\": [\"18843291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; biochemical readouts not reconstituted in vitro\", \"Genotype-phenotype range across patients limited\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Polarized basolateral localization and degradation of matrix proteins suggested a role in epithelial cell-substratum adhesion, the earliest hint of extracellular substrate function.\",\n      \"evidence\": \"Heterologous expression/immunolocalization in Caco-2 and in vitro fibronectin/laminin cleavage\",\n      \"pmids\": [\"11573963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro cleavage not validated as physiological substrate\", \"Single-lab, heterologous system\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Domain-resolved interaction mapping showed the serine protease domain binds HAI-1 and the CUB domain binds TMEFF1, beginning to define matriptase's regulatory and binding partners.\",\n      \"evidence\": \"GST pull-down, qRT-PCR and homology modeling in RKO/MCF7 cells\",\n      \"pmids\": [\"16407223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of TMEFF1 interaction unclear\", \"Pull-downs not reciprocally validated in vivo\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Engineered scFv inhibitors with mapped active-site epitopes established that matriptase is druggable at the S1 substrate-binding site, providing mechanistic tools.\",\n      \"evidence\": \"Kinetic inhibition assays and alanine-scanning mutagenesis of active-site loops\",\n      \"pmids\": [\"17475279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic efficacy in vivo not addressed here\", \"Specificity against related proteases not detailed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Gain/loss-of-function in breast cancer cells linked ST14 to cell-cycle restraint via p27/cyclin E-CDK2, indicating context-dependent anti-proliferative effects independent of miR-27b.\",\n      \"evidence\": \"Overexpression/knockdown with flow cytometry, Western blot and luciferase reporter\",\n      \"pmids\": [\"19546220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether protease activity mediates the cell-cycle effect not resolved\", \"Reconciliation with pro-metastatic roles unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of Tie2 as a cleaved substrate and of shed soluble matriptase as a proangiogenic factor connected the protease to vascular remodeling and metastatic dissemination.\",\n      \"evidence\": \"Co-IP, in vitro cleavage, shRNA knockdown, transendothelial migration, CAM assay and in vivo metastasis\",\n      \"pmids\": [\"21097670\", \"20652801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Tie2 cleavage vs other substrates not quantified\", \"Identity of the proangiogenic shed substrate not pinpointed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Transcriptional induction by IFN-\\u03b3 through JAK/STAT1 established a regulatory input controlling matriptase expression in immune cells and its role in macrophage transendothelial migration.\",\n      \"evidence\": \"STAT1 ChIP, JAK inhibitor, shRNA knockdown and migration assays\",\n      \"pmids\": [\"21295011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Macrophage substrate driving migration not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CDX2-dependent regulation of ST14 and SPINT1 via distinct enhancers revealed transcriptional control of the protease/inhibitor balance in intestinal cells.\",\n      \"evidence\": \"CDX2 ChIP-seq, luciferase reporters, overexpression/knockdown and qRT-PCR\",\n      \"pmids\": [\"30087389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional oncogenic consequence of altered ratio not demonstrated\", \"Cell-specific repressive vs enhancing logic not mechanistically explained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A mitochondrial pool binding ATP synthase \\u03b2 subunit via CUB/LDL motifs revealed an unexpected non-proteolytic bioenergetic function in neural stem cells.\",\n      \"evidence\": \"Fractionation, co-IP, proximity ligation, MitoTracker co-staining and Seahorse respiration with knockdown\",\n      \"pmids\": [\"30566397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mitochondrial targeting unknown\", \"Whether catalytic activity is involved unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Sequential PKC\\u03b2II/TACE shedding followed by SPPL2b intramembrane proteolysis releasing a nuclear EICD established a bidirectional signaling cascade coupling extracellular proteolysis to transcriptional reprogramming of chemokines driving metastasis.\",\n      \"evidence\": \"Inhibitor/siRNA/dominant-negative shedding analyses, SPPL2b loss/gain-of-function, fractionation, RNA-seq, antibody arrays and in vivo metastasis\",\n      \"pmids\": [\"32493324\", \"32241917\", \"25245289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear partners and DNA-binding mode of EICD undefined\", \"Direct vs indirect chemokine promoter regulation not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that environmental selenite triggers shedding and that EICD alone is sufficient to induce CCL2 secretion pinpointed the intracellular fragment as the effector of the pro-metastatic transcriptional response.\",\n      \"evidence\": \"Selenite treatment, EICD heterologous expression, shRNA knockdown, CCL2 ELISA and invasion assay in 4T1 cells\",\n      \"pmids\": [\"35950457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of selenite trigger across tissues unknown\", \"Mechanism by which EICD activates CCL2 promoter not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Knockdown and antibody blockade established matriptase as a metastasis-selective target whose inhibition spares primary tumor growth, supporting therapeutic targeting of the autocatalytic loop epitope.\",\n      \"evidence\": \"shRNA and mAb3F3 treatment in 4T1, E0771 and MMTV-PyMT models with migration assays\",\n      \"pmids\": [\"31426843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of mAb-induced inhibition not biochemically detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Kidney-specific and double knockouts showed St14 regulates ENaC subunit abundance indirectly through the co-protease CAP1/Prss8 rather than by direct ENaC cleavage, refining its role in renal sodium handling.\",\n      \"evidence\": \"Tissue-specific and double KO mice with Western blots, RNAscope, sodium balance and Na+-deprivation challenge\",\n      \"pmids\": [\"37830556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which St14 controls CAP1/Prss8 abundance unknown\", \"Physiological significance limited as sodium balance is maintained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same protease reconciles anti-proliferative, pro-metastatic, mitochondrial, and barrier-forming activities, and what governs tissue-specific substrate selection and subcellular targeting, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model integrating extracellular, intramembrane, nuclear, and mitochondrial functions\", \"Tissue-specific substrate repertoire incompletely defined\", \"Regulatory switch between tumor-suppressive and tumor-promoting outputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 9, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [15, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 12, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15, 17]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SPINT1\", \"TMEFF1\", \"TEK\", \"ADAM17\", \"SPPL2b\", \"PRSS8\", \"ATP5F1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}